Abstract: Objective To investigate the protective role of Trigonelline（Trig） on decompensated heart failure in mice and explore its possible mechanisms. Methods Transverse aortic arch constriction（TAC） surgery was used to construct a heart failure model in mice with increased cardiac afterload pressure. A total of 96 C57BL/6J mice were randomly divided into the Sham group（n=8）, Sham+Trig low-dose, medium-dose and high-dose 20, 40, 80 mg/（kg·d） group（n=8）,TAC group（n=16）, TAC+Trig low-dose, medium-dose and high-dose20, 40, 80 mg/（kg·d） group（n=16）. Samples were harvested after 8 weeks of gavage treatment. Physiological indexes（body weight, heart weight, cardiopulmonary index） of mice in each group were recorded. Echocardiography was used to detect cardiac function, and pathology was performed to analyze the level of myocardial fibrosis and the rate of cardiomyocyte apoptosis. RNA was extracted to detect the expression of atrial natriuretic peptide（ANP）, brain natriuretic peptide（BNP）, alpha-myosin heavy chain（α-MHC）, beta-myosin heavy chain（β-MHC）, and proteins were extracted to detect cardiac Smad3, transforming growth factor-beta1（TGF-β₁）, B cell lymphoma 2（Bcl-2）, pro-apoptotic Bcl-2-associated X（Bax）, and phosphatidylinositol3 kinase（PI3K）/protein kinase B（Akt） pathway. Results Compared with the Sham group, the values of left ventricular internal diameter（LVID）,left ventricular posterior wall thickness（LVPWT）, interventricular septal thickness（IVST）in TAC group mice were significantly increased, ejection fraction（EF）, fraction shortening（FS）（26.25±2.88）% vs（41.0±2.54）%,t=11.12, P＜0.001 and cardiac output（CO） were significantly decreased; myocardial interstitial and perivascular fibrosis were accumulated, and myocyte apoptosis rate was elevated; protein expressions of heart failure factors, as well as TGF-β₁, p-Smad3, Collagen Ⅰand Ⅲ were enhanced, and expression of PI3K/Akt pathway proteins were decreased（all P＜0.05）; compared with the TAC group, LVID, LVPWT, and IVST were decreased in TAC+Trig low-dose and medium-dose groups; EF, FS, and CO were increased; protein expressions of heart failure factor and TGF-β₁, p-Smad3, Collagen Ⅰand Ⅲ were decreased, while PI3K/Akt pathway proteins were up-regulated, which were more obvious with the statistical difference in TAC+Trig medium-dose group（all P＜0.05）. Myocardial interstitial and peritubular collagen fiber accumulation was inhibited, and cardiomyocyte apoptosis was decreased（all P＜0.05）. Conclusion Trig improves cardiac function, ameliorates the accumulation of myocardialinterstitial and perivascular fibrosis, and inhibits myocardial cell apoptosis of heart failure mice, which may be related to the activation of the PI3K/Akt signaling pathway.